Existing therapies for epilepsy have a variety of associated problems. For example, Epilim® (sodium valproate) is associated with liver dysfunction, including hepatic failure which has resulted in death, and has been found to interact with other drugs such as monoamine oxidase inhibitors. Drowsiness and sedation are among the side-effects on the CNS that have been noted for Epanutin® (phenytoin) and the benzodiazepine Valium® (diazepam). Drugs with the capacity to inhibit hepatic enzymes, such as cimetidine and omeprazole, have been found to reduce the clearance of benzodiazepines and can potentiate their action.
A further issue with existing anti-epilepsy treatments is patient compliance. Most of the oral treatments require repeated dosing within the day and it is not uncommon for doses to be omitted in error or inadvertently for logistical reasons.
Recent studies in humans have shown that anticonvulsant drugs have some efficacy in bipolar disorder (Scrip, No. 2484, Oct. 22nd 1999). The principal existing treatment, lithium, has drawbacks. For example, it is effective in only 50% of patients, monitoring of blood levels is required, and its use causes side-effects which lead to low compliance.
d,l-threo-methylphenidate (d,l-MPH) is available as Ritalin®. The ABPI Compendium of Data Sheets and Summaries of Product Characteristics (1999-2000) states that “Ritalin should be used with caution in patients with epilepsy as clinical evidence has shown that it can cause an increase in seizure frequency in a small number of such patients”. See also the US Physicians' Desk Reference.
Patrick et al, J. Pharm. Exp. Ther. 24:152-158 (1987), indicates that the pharmacological action of d,l-MPH in the treatment of attention-deficit hyperactivity disorder (ADHD) is the property of the d-enantiomer (d-MPH), as no action on the part of the l-enantiomer (l-MPH) has been detected; see also Srinivas et al, Clin. Pharm. Ther. 52:561-8 (1992). It has also been found that, following oral dosing, the l-enantiomer is metabolised preferentially, such that plasma levels of the d-enantiomer are generally found to be higher than those of the l-enantiomer (Aoyama et al, Eur. J. Clin. Pharm. 44:79-84 (1993); Hubbard et al, J. Pharm. Sci. 78:944-7 (1989)), and that very little l-MPH enters the circulation or becomes available to the brain.
Intravenous administration of d,l-MPH has shown similar plasma levels of the two enantiomers for around 1.5 hours after dosing, after which the levels diverge (Srinivas, Pharm. Res. 10:14-21 (1993)). Ding et al, Psychopharmacology 131:71-78 (1997), has shown that l-MPH is detected in the brain after intravenous dosing.
WO-A-99/30694 discloses the topical application of d,l-MPH, using substantially zero order kinetics. An example of a topical composition comprises the drug in an adhesive base.